title: DNA cleavage and 8-hydroxydeoxyguanosine formation caused by tamoxifen derivatives in vitro.
abstract: DNA damage caused by tamoxifen and its derivatives was examined by estimating the conversion of supercoiled pUC18 plasmid DNA to linear form by means of agarose gel electrophoresis. N-Desmethyltamoxifen induced DNA cleavage and its effect was enhanced by the addition of reducing agents such as dithiothreitol, NADPH and 2-mercaptoethanol. 4-Hydroxytamoxifen itself had little effect, but the cleavage was slightly enhanced by the addition of reducing agents. DNA damage was higher with alpha-hydroxytoremifene than with alpha-hydroxytamoxifen, which had a prominent effect only at high concentration. The cleavage by alpha-hydroxy derivatives were not enhanced by reducing agents. No damage was induced by tamoxifen, toremifene, 3-hydroxytamoxifen or N-desmethyltoremifene. The DNA cleavage by N-desmethyltamoxifen was inhibited by the addition of EDTA, mannitol, sodium azide, methionine, catalase and superoxide dismutase. The formation of 8-hydroxy-2'-deoxyguanosine was also examined with calf thymus DNA in vitro. A slight increase of its level was found with 4-hydroxytamoxifen in the presence of dithiothreitol and also with N-desmethyltamoxifen in the presence of NADPH, but alpha-hydroxytoremifene and alpha-hydroxytamoxifen were ineffective. These experimental data suggest that among metabolites of tamoxifen, N-desmethyltamoxifen and probably also 4-hydroxytamoxifen cause oxidative DNA damage in which redox cycling is involved. The DNA damage by alpha-hydroxytoremifene appears to involve a different mechanism from that by N-desmethyltamoxifen. Tamoxifen and toremifene are possibly metabolized to the forms contributing to DNA damage.
authors.affiliation: Department of Toxicology, The Tokyo Metropolitan Research Laboratory of Public Health, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okubo
authors.forename: F
authors.initials: F
authors.lastname: Nagai
authors.forename: K
authors.initials: K
authors.lastname: Ushiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: S
authors.initials: S
authors.lastname: Ozawa
authors.forename: K
authors.initials: K
authors.lastname: Kano
authors.forename: S
authors.initials: S
authors.lastname: Tomita
authors.forename: H
authors.initials: H
authors.lastname: Kubo
authors.forename: I
authors.initials: I
authors.lastname: Kano
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D004247:DNA / Q000187:drug effects*; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004965:Estrogen Antagonists / Q000633:toxicity*; D013629:Tamoxifen / Q000633:toxicity*
chemical_list: D018736:DNA Adducts; D004965:Estrogen Antagonists; D013629:Tamoxifen; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine